Androgen receptor (AR), a member of the steroid receptor super-family, is a ligand-dependent transcription factor that mediates androgen action in cells. The AR is widely distributed among cardiac muscle, skeletal and smooth muscle, gastrointestinal vesicular thyroid follicular cells, adrenal cortex, liver, pineal, and numerous brain cortical and subcortical regions, including spinal motor neurons. AR is composed of three major domains: an NH2-terminal transcriptional activation domain, a central DNA-binding domain, and a COOH-terminal ligand-binding domain. After binding to androgens, AR translocates to the nucleus and regulates expression of AR target reproductive and non-reproductive tissues, including the prostate and seminal vesicles, male and female external genitalia, skin, testis, ovary, cartilage, sebaceous glands, hair follicles, sweat glands, genes. [Gelmann E. P. J Clin Oncol 2002, 20, 3001-15; Heinlein, C. A.; Chang, C. Endocr Rev 2004, 25, 276-308] AR hypersensitivity, as a result of AR gene mutation and/or amplification, overexpression of coactivators, often occurs and plays crucial roles in prostate cancer development, progression, and androgen-independent growth. [Heinlein, C. A.; Chang, C. Endocr Rev 2004, 25, 276-308; Chen, C. D et al., Nat Med., 2004; 10, 33-9; Isaacs, J. T.; Isaacs, W. B. Nat. Med. 2004; 10, 26-7] Therefore, in most cases advanced prostate cancer, one of the leading cause of cancer death in men after lung cancer, it has been directly linked to the androgen receptor (AR). Most prostatic tumors are stimulated to grow by androgens, and consequently androgen withdrawal is a well-established therapy for prostate cancer treatment. Androgen deprivation therapies consist of surgical castration, through orchiectomy or medical castration by administration of a luteinising hormone-releasing hormone analogue (LHRH-A), such as goserelin [Kirby, R. S. Crit J Clin Pract 1996; 50, 88-93](Zoladex™, AstraZenaca). However, although castration removes androgen release from the testes, androgen biosynthesis in the adrenals (8±10% of total circulating androgens) is not affected. [Geller J. The role of adrenal androgens in prostate cancer in: Pasqualini J. R., Katzenellenbogen, B. S. (eds). Hormone-Dependent Cancer. Marcel Dekker: New York, 1996, 289-305] Because of this, a widely used management strategy for advanced prostate cancer is a combination of surgical or chemical castration and administration of antiandrogens. [Labrie, F.; et al., Clin Invest Med 1982; 5, 267-275] Antiandrogens bind to the AR and inhibit all androgens at the target cell level. In particular, antiandrogens compete with endogenous androgens for binding sites of the androgen receptors in the prostate cell nucleus, thereby promoting apoptosis and inhibiting prostate cancer growth. By contrast with androgens, however, the receptor-antiandrogen complex is unstable so that gene transcription and protein synthesis are not stimulated. [Gaillard-Moguilewsky, M. Urology 1991, 37 (Suppl), 5-12]
Ideally, an antiandrogen should possess high specificity and affinity for the androgen receptor, being devoid of other hormonal or anti-hormonal activity. Antiandrogens act by two primary mechanisms: inhibition of ligand (androgen) binding to the AR, and inhibition of androgen-independent activation of the receptor. It is more accurate to refer to these compounds as androgen-receptor antagonists, since they inhibit activation, whether this is androgen-mediated or not. There are two structurally distinct types of antiandrogen, i.e. steroidal and non-steroidal. One steroidal and three non-steroidal antiandrogens are in common use for the treatment of prostate cancer. However, the use of the steroidal agent cyproterone acetate (CPA), a synthetic derivative of hydroxyprogesterone, is limited since, in addition to blocking androgen receptors, has progestational and antigonadotrophic properties. [Furr, B. J. A.; Kaisary, A. V. Treatment: hormonal manipulation: Antiandrogens. In Kaisary, A. V.; et al., eds. Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment. London: Martin Dunitz, 1999: 277-90]
CPA therefore inhibits the release of LH, decreasing serum testosterone levels, and causing a severe suppression of libido and loss of erectile potency. The nonsteroidal antiandrogens, bicalutamide, flutamide and nilutamide are pure antiandrogens, which exert their effects through competitive inhibition of the binding of testosterone, and its metabolite 5-α dihydrotestosterone (5α-DHT), to the nuclear androgen receptor. As testosterone levels are not blocked by nonsteroidal antiandrogens, [Gaillard-Moguilewsky, M. Urology 1991, 37 (Suppl), 5-12] these drugs offer the possibility of maintaining sexual interest and potency. Within the class of non-steroidal anti-androgens, there is variation in the degree to which ligand-independent activation is inhibited. Preclinical data suggest that non-steroidal antiandrogen bicalutamide may be a more effective drug in the treatment of prostate cancer with respect to flutamide and nilutamide. [Tucker, H.; et al., J. Med. Chem., 1988, 31, 954-959]
The endocrine therapy using non-steroidal antiandrogens and LHRH analogs is initially very effective but is time-limited. Nearly half of all patients with these tumors develop resistance to this therapy after several years, suggesting the development of androgen-independent prostate cancer cells or the ability of adrenal androgens to support tumor growth. This leads to serious clinical inconveniences. [Oh, W. K.; Kantoff, P. W. J Urol 1998, 160, 1220-1229]
Surprisingly, clinical benefit has been observed following the withdrawal of anti-androgens (Anti-Androgen Withdrawal Response, AAWR) in a subset of prostate cancer patients with therapy-resistant disease. [Scher, H. I.; Kolvenbag, G. J. Eur Urol., 1997, 31, 3-7] The anti-androgen withdrawal event indicate that there may be clinically relevant changes in AR expression and function during long-term androgen ablation which can be in part attributed to mutant ARs detected in prostatic carcinomas. For example, bicalutamide that acts as a pure antagonist in parental LNCaP cells, showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. [Culig, Z. et al., British J. of Cancer 1999, 81, 242-251] However, alternative mechanisms may also be considered. In fact, it has been found that non-steroidal antiandrogens act as AF-1 agonists under conditions of high AR protein expression. This partial antagonistic property of antiandrogens may be a molecular mechanism by which prostate cancer develops resistance to these drugs. [Fuse, H et al., The Prostate, 2007, 67, 630-637] These findings may have repercussions on the natural course of prostate cancer with androgen deprivation and on strategies of therapeutic intervention. For this reason, secondary treatment to block androgen receptors in a primary, secondary or tertiary manner has been developed. Secondary hormonal manipulations for affected patients include antiandrogen withdrawal, second-line antiandrogens, [Kojima, S. et al., J Urol. 2004, 171, 679-683] direct adrenal androgen inhibitors (aminoglutethimide, ketoconazole), [Mahler, C.; Verhelst, J.; Denis, Cancer, 1993, 71, 1068; Sartor, O et al., J. Natl. Cancer Inst. 1944, 86, 222] corticosteroids (e.g.: mitoxantone), [Tannock, I. F et al., J. Clin. Oncol. 1996, 14, 1756] estrogens [Ferro, M. A. et al., Urology 1989, 34: 134] and progestins. More recently, new classes of antiandrogens have been investigated. These compounds have not yet clinically been evaluated, but demonstrate potent antiandrogenic activity in in vitro and preclinical models. Selected examples are: a) Bicyclic-1H-isoindole-1,3-(2H)-dione analogues which can be considered as tructurally modified of nilutamide analogues. [Salvati, M. E. et al., Bioorg. Med. Chem. Lett. 2005, 15, 389] b) quinolone derivatives with a linear tricyclic pharmacophore, 2(1H)-piperidino[3,2-g]quinolinone. [Hamann, L. G. et al., J. Med. Chem. 1998, 41, 623] c) androgen receptor antagonists containing a carborane moiety as a hydrophobic skeletal structure. These compounds bind to AR and show antiandrogenic activity towards androgen-dependent SC-3 cells with almost the same potency as the known anti-androgen hydroxyflutamide. [Fujii, S. et al., Bioorg. Med. Chem. Lett. 2005, 15, 227-230] d) β-Alkylthio indolyl carbinols [Lanter, J. C.; et al., Bioorg. Med. Chem. Lett. 2007, 17, 2545-2548] e) Phenotiazine derivatives. [Bisson, W. H. et al. PNAS, 2007, 104, 11927-11932] Although these nonsteroidal antiandrogens exhibit high specificity for AR and are orally available, they do not possess tissue selectivity. Along with the blockade of AR action in the prostate, antiandrogens also block AR actions in other target tissues, including anabolic tissues (e.g., skeletal muscle and bone) and the hypothalamus-pituitary-testis axis.
In the past several years, a new class of non-steroid molecules targeting the androgen receptors has emerged. [Zhi, L.; Martinborough, E. Annu. Rep. Med. Chem. 2001, 36, 169; Negro-Vilar, A. J. Clin. Endocrinol. Metab. 1999, 84, 3459] For these molecules the term of selective androgen receptor modulators (SARMs) has been chosen after the discovery of similar molecules, the selective estrogen receptor modulators (SERMs), which targets the estrogen receptors. SARMs selectively bind and modulate ARs depending on tissue type. The goal of research in this area is to allow a customized response, namely, tissues that are the target of the therapy will respond as they would to testosterone; other tissues, where undesirable side effects are produced, will not. For an ideal selective androgen receptor modulator, the antagonist or weak agonist activity in the prostate will not stimulate nascent or undetected prostate cancer; while the strong agonist activity can be, exploited to stimulate testosterone's beneficial action in bone, muscle and brain, either cross or not cross into the central nervous system to affect lipids. Because of these properties, SARMs could be developed to treat a range of medical conditions and physiological functions. Potential indications are: andropause conditions of aging [Tenover, J. L. J Androl 1997, 18, 103-106] (hypogonadism, sarcopenia, osteoporosis, high cholesterol); disorders of the nervous central system (low libido, depression and mood); male reproduction [Wu, F. C. Baillieres Clin. Endocrinol. Metab. 1992, 6, 373-403] (infertility, male contraception, erectile dysfunction); wasting conditions associated with disease and trauma (cancer, AIDS); end stage of renal disease; severe burns; prostate disorders (BPH, prostate cancer) and other conditions (anaemia, obesity, high cholesterol, hair loss). Structural modifications of bicalutamide led to the discovery of selective androgen receptor modulators. Lead compounds (S)-3-(4-acetylphenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide and (S)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-(4-propionylphenoxy)propanamide, which not only bind AR with high affinity, but also demonstrate tissue selectivity in animal models. [Yin, D. et al., J. Pharmacol. Exp. Ther. 2003, 304, 1334-1340; Gao, W. et al., Endocrinology 2004, 145, 5420-5428]
Quite interestingly, in intact male rats, (S)-3-(4-acetylphenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide and (S)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)-phenyl]-3-(4-propionylphenoxy)propanamide behaved as antagonists in the prostate without reducing the anabolic effects of androgens, thus suggesting that selective androgen receptor modulators with low intrinsic activity in the prostate, might serve as an alternative therapy for benign prostate hyperplasia (BPH) or even prostate cancer. For this reason, the AR binding ability and in vitro functional activity and the structure-activity relationships (SARs) of a series of non-steroidal compounds derived from bicalutamide was examined. [He, Y. et al., Eur. J. Med. Chem. 2002, 37, 619-634; Yin, D. et al., Mol. Pharmacol. 2003, 63, 211-223] These studies demonstrated that non-steroidal ligands can be structurally modified from known non-steroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. The conclusion was that the overall effect on AR binding affinities, as well as, their abilities to stimulate AR-mediated transcriptional activation is determined, by a delicate balance of factors, including nature, size, and position of the substituent.
There is a need for new compounds having desirable pharmacological properties, and synthetic pathways for preparing them. Because activities are very sensitive to small structural changes, one compound may be effective in treating prostate cancer, whereas a second compound may be effective in treating other AR related pathologies, such as: male contraception, treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline an Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, hypogonodism, osteoporosis, hair loss, anemia, erectile dysfunctions, obesity, sarcopenia, osteopenia, benign prostate hyperplasia, alterations in mood and cognition; treatment of conditions associated with AIDF, such as sexual dysfunction, decreased sexual libido, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; treatment and/or prevention of chronic muscular wasting.
Therefore, the aim of the present invention is to provide compounds, their synthesis and their pharmaceutically acceptable preparations, which are useful in the treatment of the above mentioned pathologies.